My laboratory conducts basic research investigating the molecular mechanisms that regulate cell growth and survival, specifically in mammary epithelial and breast tumor cells. We use mouse models and cells derived from these animals to characterize the molecular signaling pathways in tumor cells and in normal mammary epithelial cells within the mammary gland life cycle. We also study signaling pathways in human breast tumor cells in vitro, and we analyze patient samples to determine the clinical relevance of our observations. Specifically, we use the C/EBPdelta transcription factor as a molecular tool. Gene expression analyses in human tumors and genetic studies in cell lines in vitro strongly suggest that C/EBPdelta is a tumor suppressor gene. Our previous contributions to this model were the findings that C/EBPdelta augments genomic stability in mouse embryo fibroblasts in culture (Huang et al., 2004), and that C/EBPdelta promotes cell death of mouse mammary epithelial cells during postlactational involution (Thangaraju et al., 2005). Our subsequent investigations have been focused on characterizing the specific molecular mechanisms by which C/EBPdelta exerts tumor suppressor activity. We have discovered that C/EBPdelta induces the expression of the Cdc27/APC3 subunit of the anaphase promoting complex/cyclosome (APC/C), which in turn results in degradation of the pro-oncogenic cell cycle regulator cyclin D1. Like C/EBPdelta, and in contrast to cyclin D1, we find that Cdc27 is downregulated in several breast cancer cell lines, suggesting that Cdc27 itself may be a tumor suppressor (Pawar et al., 2010, Proc. Natl. Acad. Sci. USA 107(20):9210-5. Analysis of proteins interacting with C/EBPdelta led to the discovery that C/EBPdelta interacts with Fanconi anemia D2 (FANCD2), a protein involved in replication associated DNA repair. C/EBPdelta augments DNA repair by facilitating the interaction of FANCD2 with importin 4 and, as a result, the nuclear import of FANCD2. This study identified a novel non-transcriptional activity of C/EBPdelta, and revealed a new molecular mechanism for its tumor suppressor function (Wang et al., 2010, Proc. Natl. Acad. Sci. USA, 107(37):16131-6). We used transgenic mice overexpressing the Neu/HER2/ERBB2 proto-oncogene in the mammary gland to confirm for the first time in an animal model that C/EBPdelta can function as a tumor suppressor. Surprisingly, this study also revealed that C/EBPdelta is necessary for efficient tumor metastasis. We found that C/EBPdelta expression is induced by hypoxia and that C/EBPdelta inhibits expression of the tumor suppressor FBXW7, thereby augmenting the mTOR/AKT/S6K/HIF-1 pathway. These findings define a role for C/EBPdelta in metastasis promotion despite its primary tumor suppressor activity. Hence, C/EBPdelta is a new example for the TGF-beta paradox of cancer progression, acting as a tumor suppressor at early stages and promoting metastasis at later stages (Balamurugan et al., 2010, EMBO J.29(24):4106-17). Tumor metastasis is the most serious challenge for managing cancer as a chronic disease. A better understanding of the basic biology of metastatic progression and the requirements of metastatic cells for growth and survival is pivotal for future therapeutic advances. We have identified pro- and anti-metastatic activities of C/EBPdelta. Therefore, the focus of the groups current investigations is on promoting our understanding of these seemingly contradictory activities: (a) to decipher the functions of C/EBPdelta at different stages of metastatic progression, (b) to investigate the role of C/EBPdelta in mesenchymal to epithelial transition, (c) to characterize the role of C/EBPdelta in the cellular response to chemotherapeutics, (d) to identify the target genes and molecules mediating these effects of C/EBPdelta, and (e) we continue to use C/EBPdelta-deficient mice to investigate signaling pathways that regulate mammary development and tumorigenesis.